Compositions and methods relating to resveratrol

ABSTRACT

The present invention relates to compositions and methods comprising resveratrol and uses thereof. Some embodiments include compositions and methods with increased bioavailability of resveratrol. Certain embodiments include compositions comprising resveratrol and a solubilizer. Particular embodiments include transmucosal delivery of resveratrol from the composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 14/691,320(filed Apr. 20, 2015). U.S. Ser. No. 14/691,320 is a divisionalapplication of U.S. Ser. No. 12/955,810 (now U.S. Pat. No. 9,125,858),filed Nov. 29, 2010. U.S. Ser. No. 12/955,810 is a non-provisionalapplication claiming priority to U.S. Provisional Application No.61/265,035, filed Nov. 30, 2009. The disclosure of each of the aboveapplications is incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compositions and methods comprisingresveratrol and uses thereof. Some embodiments include compositions andmethods with increased bioavailability of resveratrol. Certainembodiments include compositions comprising resveratrol and asolubilizer. Particular embodiments include transmucosal delivery ofcompositions.

BACKGROUND OF THE INVENTION

Resveratrol is a polyphenolic compound found in several plants. Thecompound includes double bonds and exists in two isoforms,trans-resveratrol and cis-resveratrol. The trans-isomer is the lessstable form: trans to cis isomerization is facilitated by UV light andhigh pH, the cis to trans conversion is facilitated by low pH.

Resveratrol has extensive biological properties, includinganticarcinogenic, anti-inflammatory, and estrogenic activities as wellas cardiovascular protection, free-radical scavenging,inhibition/induction of apoptosis, and inhibition of plateletaggregation (See e.g., Mehdi S. et al., “Resveratrol addiction: To dieor not to die.” Mol. Nutr. Food Res. 2009, 53, 115-128; Baur J. et al.,“Therapeutic potential of resveratrol: the in vivo evidence.” NatureReviews 5:493-506; and Ellen L. Robb and Jeffrey A. Stuart,“trans-Resveratrol as A Neuroprotectant.” Molecules 2010, 15, 1196-1212,and references therein in each). For example, resveratrol has been shownto exhibit in vitro as well as in vivo chemopreventive andchemotherapeutic activities (Delmas, D., et al., “Resveratrol as achemopreventive agent: A promising molecule for fighting cancer” Curr.Drug Targets 2006, 7, 423-442). Indeed, resveratrol has been shown toexhibit chemopreventive and chemotherapeutic activities in all threestages of carcinogenesis (i.e., initiation, promotion, and progression)(de la Lastra, C. A., Villegas, I., Resveratrol as an anti-inflammatoryand anti-aging agent: Mechanisms and clinical implications, Mol. Nutr.Food Res. 2005, 49, 405-430). Chronic inflammation can lead to cancer,diabetes, and cardiovascular, pulmonary, and neurological diseases. Oneof the possible mechanisms for the protective activities of resveratrolis downregulation of inflammatory responses. Resveratrol has been shownto inhibit inflammatory responses through the inhibition of synthesis ofvarious proinflammatory mediators, modulation of prostaglandinsynthesis, and through the inhibition of factors such as IL-β, NF-κB,and AP-1 (Das, S., et al., “Resveratrol: A therapeutic promise forcardiovascular diseases” Recent Patents Cardiovasc. Drug Discov. 2007,2, 133-138). Resveratrol protects the cardiovascular system in amultidimensional way. One effect includes inhibition of apoptotic celldeath at very low concentrations, thereby providing protection fromvarious diseases including myocardial ischemic reperfusion injury,atherosclerosis, and ventricular arrhythmias.

In rodents, resveratrol is absorbed mainly in the duodenum; studies inrat intestine indicate that approximately 20% of available resveratrolis absorbed. In such studies, the majority of the absorbed resveratrolwas detected in plasma as conjugated derivatives, while only a minuteamount was detected in an unconjugated form. (Andlauer, W., et al.,Assessment of resveratrol bioavailability in the perfused smallintestine of the rat, Drugs Exp. Clin. Res. 2000, 26, 47-55). In humans,resveratrol is glucuronated in the liver and sulfated in both the liverand the duodenum (Aggarwal, B. B., et al., Role of resveratrol inprevention and therapy of cancer: Preclinical and clinical studies,Anticancer Res. 2004, 24, 2783-2840). The major derivatives ofresveratrol glucuronidation are trans-resveratrol-3-O-glucuronide,trans-resveratrol-4′-O-glucuronide, and trans-resveratrol-3-O-sulfate(Yu, C., et al., Human, rat, and mouse metabolism of resveratrol, Pharm.Res. 2002, 19, 1907-1914). Kinetic analysis of resveratroltransformation suggests that, in the liver, glucuronidation is favoredover sulfation, with similar rates of reaction.

In one study in humans, the bulk of an intravenous dose of resveratrolwas converted to sulphate and gluconorated conjugates during absorption.(Walle, T., et al. High absorption but very low bioavailability of oralresveratrol in humans. Drug Metab. Dispos. 32, 1377-1382 (2004)). Ananalysis of plasma metabolites after oral dosing detected both sulphateand glucuronide conjugates. Five distinct metabolites were present inthe urine, including, resveratrol monosulphate, two isomeric forms ofresveratrol monoglucuronide, dihydroresveratrol monosulphate anddihydroresveratrol monoglucuronide. It is well known that modificationssuch as glucuronidation and sulphation reduce the cell permeability ofsmall molecules and aid in their excretion. This extensive modificationby the small intestine and liver during absorption greatly reduce thebioavailability of resveratrol.

SUMMARY OF THE INVENTION

The present invention relates to compositions and methods comprisingresveratrol and uses thereof. Some embodiments include compositions andmethods with increased bioavailability of resveratrol. Certainembodiments include compositions comprising resveratrol and asolubilizer. Particular embodiments include transmucosal delivery ofcompositions.

Some embodiments include methods of administering resveratrol to asubject. Some such methods include administering a solid or semi-solidpharmaceutical composition comprising resveratrol and a solubilizer,wherein the administering comprises the subject retaining thecomposition in its mouth for sufficient amount of time for oraltransmucosal absorption of resveratrol.

In some embodiments, the solubilizer is selected from a co-solvent and acomplexer. In some embodiments, the solubilizer comprises a sugar. Insome embodiments, sugar comprises a monosaccharide. In some embodiments,the sugar is selected from the group consisting of ribose,2-deoxyribose, deoxyribose, arabanose, ribulose, deoxyarabanose, xylose,deoxyxylose, fructose, deoxyfructose, and mixtures thereof. In someembodiments, the solubilizer comprises ribose. In some embodiments, thecomplexer comprises nicotinamide. In some embodiments, complexer forms anon-covalent stoichiometric association of two or more molecules withthe resveratrol. In some embodiments, the co-solvent increases aqueoussolubility of resveratrol by acting as a chaotrope and disrupting themolecular interactions of water. In some embodiments, the solubilizercomprises a sequestered hydrophobic region and a hydrophilic region.

In some embodiments, the resveratrol comprises trans-resveratrol.

In some embodiments, the composition is retained in the mouth for atleast 5 minutes. In some embodiments, the composition is retained in themouth for at least 10 minutes.

In some embodiments, the composition comprises a pH adjusting substance.In some embodiments, the pH adjusting substance comprises an acid. Insome embodiments, the composition has an acidic pH.

In some embodiments, the solubilizer is in the range of about 2% toabout 99% by weight of the composition.

In some embodiments, the administering comprises administering thecomposition via a route selected from the group consisting of bucal,sublingual, and gingival. In some embodiments, the administeringcomprises bucal administration. In some embodiments, the administeringis comprises sublingual administration. In some embodiments, theadministering is comprises gingival administration.

In some embodiments, the resveratrol is in the range from about 1% toabout 50% by weight of the composition. In some embodiments, thesolubilizer is in the range from about 5% to about 95% by weight of thecomposition.

In some embodiments, the subject is a mammal (e.g., a human).

In some embodiments, the composition comprises a dosage form selectedfrom the group consisting of tablet, lozenge, semisolid lozenge, taffy,thin film, pressure capsule, and freeze dried solid. In someembodiments, the composition comprises a dosage form selected from thegroup consisting of taffy, tablet, lozenge, or thin film.

In some embodiments, the composition comprises about 5 mg to about 1000mg resveratrol. In some embodiments, the composition has a weight ofabout 10 mg to about 5000 mg.

In some embodiments, the composition further comprises a coating,wherein the coating is impermeable to light.

In some embodiments, the composition enhances the stability ofresveratrol to the trans isomer as compared to resveratrol without thesolubilizer.

In some embodiments, the composition enhances the flavor of resveratrolin the composition as compared to resveratrol without the solubilizer.

In some embodiments, the administering is at least daily.

In some embodiments, the composition further comprises at least oneadditional component selected from the group consisting of coatings,sweeteners, thickeners, preservatives, colorings, flavorings, binders,cosmetic additives, and penetration enhancers. In some embodiments, thesweetener is selected from the group consisting of glucose, fructose,and tagatose. In some embodiments, the thickener is selected from thegroup consisting of polysaccharides, starches, vegetable gums, lectins,pectin, and proteins. In some embodiments, the preservative is selectedfrom the group consisting of calcium propionate, sodium nitrate, sodiumnitrite, sulfites disodium EDTA, butylated hydroxyanisole, and butylatedhydroxytoluene. In some embodiments, the coloring is selected from thegroup consisting of E150, Annato E160b, E40, Betanin, Pandan, FD&C BlueNo. 1, and FD&C Red No. 40. In some embodiments, the flavoring isselected from the group consisting of cinnamon, spearmint, and cherry.In some embodiments, the binder is selected from the group consisting ofgum Arabic, gum tragacanth, gelatin, starch, dextrose, and mixturesthereof. In some embodiments, the cosmetic additive is selected from thegroup consisting of flavor crystals, and flavor maskers. In someembodiments, the penetration enhancer is selected from the groupconsisting of bile salts, surfactants, fatty acids, fatty acidderivatives, chelators, and chitosan.

In some embodiments, the composition comprises 100 mg resveratrol. Insome embodiments, the administering achieves a serum C_(max) ofresveratrol greater than about 21 ng/ml. In some embodiments, theadministering achieves an area under serum concentration (AUC) ofresveratrol greater than about 19.5 ng*hr/ml.

In some embodiments, the administering achieves an improvedbioavailability of the resveratrol compared to the bioavailability ofresveratrol administered without the solubilizer. In some embodiments,the improved bioavailability comprises an increase in serum C_(max) ofresveratrol compared to the serum C_(max) of resveratrol for resveratroladministered without the solubilizer. In some embodiments, the increasein serum C_(max) is at least a 10%. In some embodiments, the increase inserum C_(max) is at least 50% In some embodiments, the improvedbioavailability comprises an increase in area under serum concentration(AUC) of resveratrol compared to the area under serum concentration(AUC) of resveratrol for resveratrol administered without thesolubilizer. In some embodiments, the increase is at least 10%. In someembodiments, the increase is at least 50%.

In some embodiments, the resveratrol administered without thesolubilizer lacks sulfertransferase or glucotransferase inhibitors. Insome embodiments, the reserveratol administered without the solubilizeris administered with a pharmaceutically accepted drug release compound.In some embodiments, the pharmaceutically accepted drug release compoundcomprises a cyclodextrin. In some embodiments, the improvedbioavailability is statistically significant.

In some embodiments, the amount of the resveratrol to the solubilizer isin the range of about 5 mg/g to about 500 mg/g. In some embodiments, theamount of the resveratrol to the solubilizer is in the range of about 20mg/g to about 100 mg/g.

In addition to the foregoing methods, some embodiments includepharmaceutical compositions. Some such pharmaceutical compositionsinclude resveratrol and a solubilizer in solid or semi-solid form.

In some embodiments, the solubilizer is selected from a co-solvent and acomplexer. In some embodiments, the solubilizer comprises a sugar. Insome embodiments, the sugar comprises a monosaccharide. In someembodiments, the sugar is selected from the group consisting of ribose,2-deoxyribose, deoxyribose, arabanose, ribulose, deoxyarabanose, xylose,deoxyxylose, fructose, deoxyfructose, and mixtures thereof. In someembodiments, the solubilizer comprises ribose. In some embodiments, thecomplexer comprises nicotinamide. In some embodiments, the complexerforms a non-covalent stoichiometric association of two or more moleculeswith the resveratrol. In some embodiments, co-solvent increases aqueoussolubility of resveratrol by acting as a chaotrope and disrupting themolecular interactions of water. In some embodiments, the solubilizercomprises a sequestered hydrophobic region and a hydrophilic region.

In some embodiments, the resveratrol comprises trans-resveratrol.

In some embodiments, the composition comprises a pH adjusting substance.In some embodiments, the pH adjusting substance comprises an acid. Insome embodiments, the composition has an acidic pH.

In some embodiments, the percentage weight of the solubilizer is in therange of about 2% to about 99% of the composition. In some embodiments,the resveratrol comprises from about 1% to about 50% of the composition.In some embodiments, the solubilizer comprises about 5% to about 95% ofthe composition.

In some embodiments, the composition further comprises at least oneadditional component selected from the group consisting of coatings,sweeteners, thickeners, preservatives, colorings, flavorings, binders,cosmetic additives, and penetration enhancers. In some embodiments, thesweetener is selected from the group consisting of glucose, fructose,and tagatose. In some embodiments, the thickener is selected from thegroup consisting of polysaccharides, starches, vegetable gums, lectin,pectin, and proteins. In some embodiments, the preservative is selectedfrom the group consisting of calcium propionate, sodium nitrate, sodiumnitrite, sulfites disodium EDTA, butylated hydroxyanisole, and butylatedhydroxytoluene. In some embodiments, the coloring is selected from thegroup consisting of E150, Annato E160b, E40, Betanin, Pandan, FD&C BlueNo. 1, and FD&C Red No. 40. In some embodiments, the flavoring isselected from the group consisting of cinnamon, spearmint, and cherry.In some embodiments, the binder is selected from the group consisting ofgum Arabic, gum tragacanth, gelatin, starch, dextrose, and mixturesthereof. In some embodiments, the cosmetic additive is selected from thegroup consisting of flavor crystals, and flavor maskers. In someembodiments, the penetration_enhancer is selected from the groupconsisting of bile salts, surfactants, fatty acids, fatty acidderivatives, chelators, and chitosan.

In some embodiments, the composition comprises at least about 100 mgresveratrol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows U.V-HPLC and MS spectral traces for 1.6 mg resveratrol in 1ml water. PDA-316 nm panel: trans isomer detected at peak, cis isomer isnot detected (NL: 1.39E6; nm=315.5-316.5; PDA Avalon). PDA-284 nm panel:NL: 9.15E5; nm=283.5-284.5; PDA Avalon. MS Panel: NL: 2.8E6;m/z=226.60-227.60; F: -c APCI corona; sid=10.00 Full ms [100.00-1000.00]MS ICIS. Tandem MS panel: NL: 4.13E5; m/z=184.50-185.50; F: -c APCIcorona; sid=10.00; Full ms2 227.00@cid45.00 [60.00-250.00] MS ICIS.

FIG. 2 shows U.V-HPLC and MS spectral traces for 1.6 mg resveratrol in 1ml 3 M ribose. PDA-316 nm panel: trans isomer detected at peak, cisisomer is not detected. NL: 2.16E6; nm=315.5-316.5; PDA Avalon. PDA-284nm panel: NL: 1.44E6; nm=283.5-284.5; PDA Avalon. MS Panel: NL: 5.17E6;m/z=226.60-227.60; F: -c APCI corona; sid=10.00 Full ms [100.00-1000.00]MS ICIS. Tandem MS panel: NL: 8.96E5; m/z=184.50-185.50; F: -c APCIcorona; sid=10.00; Full ms2 227.00@cid45.00 [60.00-250.00] MS ICIS.

FIG. 3 shows U.V-HPLC and MS spectral traces for 1.6 mg resveratrol in 1ml water exposed to U.V. light for 30 minutes. PDA-316 nm panel: transisomer and cis isomer peaks detected; NL: 5.05E5; nm=315.5-316.5; PDAAvalon. PDA-284 nm panel: NL: 4.31E5; nm=283.5-284.5; PDA Avalon. MSPanel: NL: 3.90E6; m/z=226.60-227.60; F: -c APCI corona; sid=10.00; Fullms [100.00-1000.00] MS ICIS. Tandem MS panel: NL: 7.71E5;m/z=184.50-185.50; F: -c APCI corona; sid=10.00 Full ms2 227.00@cid45.00[60.00-250.00] MS ICIS.

FIG. 4 shows U.V-HPLC and MS spectral traces for 1.6 mg resveratrol in 1ml 3 M ribose exposed to U.V. light for 30 minutes. PDA-316 nm panel:trans isomer and cis isomer peaks detected. NL: 1.30E6; nm=315.5-316.5;PDA Avalon. PDA-284 nm panel: NL: 8.58E5; nm=283.5-284.5; PDA Avalon. MSPanel: NL: 6.51E6; m/z=226.60 227.60; F: -c APCI corona; sid=10.00 Fullms [100.00-1000.00] MS ICIS. Tandem MS panel: NL: 1.27E6;m/z=184.50-185.50; F: -c APCI corona; sid=10.00 Full ms2 227.00@cid45.00[60.00-250.00] MS ICIS.

FIG. 5 shows a graph of an estimated time-concentration profile that ispredicted for the serum concentration of resveratrol in subjectadministered a single oral dose of 1 g resveratrol.

DETAILED DESCRIPTION

The present invention relates to compositions and methods comprisingresveratrol and uses thereof. Some embodiments include compositions andmethods with increased solubility of resveratrol. Some embodimentsprovided herein include methods for improving the bioavailability ofresveratrol in a subject. Some embodiments include compositions andmethods with improved peak plasma levels of resveratrol in the subject.Some methods include administering a composition comprising resveratroland a solubilizer to the subject. In preferred embodiments, theadministering comprises oral transmucosal delivery.

Certain compositions and methods provided herein can be used toadminister resveratrol to a subject via the oral mucosal membranesachieving an increased bioavailability of the resveratrol. Certaincompositions include a solubilizer. Some such solubilizers increase theaqueous solubility of resveratrol allowing for oral transmucosalabsorption of the resveratrol via a subject's oral mucosal membranes.Accordingly, unconjugated resveratrol is absorbed directly into thebloodstream, without passing through the lining of the small intestines,and without being transported directly to the liver via the portal veinwhere it would also undergo extensive modification, e.g., sulfation andglucuronation.

Certain Compositions

Some compositions provided herein include resveratrol and/or analogs ofresveratrol. An example structure of resveratrol is shown in formula(I):

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) includestrans-resveratrol and cis-resveratrol. In some embodiments,trans-resveratrol is used.

Some compositions also include at least one solubilizer. As used herein,the term “solubilizer” means a compound that increases the aqueoussolubility of another compound. Solubilizers include co-solvents andcomplexers. As used herein, the term “co-solvent” means a compound thatincreases the aqueous solubility of a compound by disrupting themolecular interactions of water. While not being bound by any particulartheory, the disruption in the self-association of water leads to areduction of its ability to squeeze out non-polar hydrophobic compounds,and consequently to the enhancement of the solubility of non-polarsolutes. A co-solvent increases the aqueous solubility of a hydrophobicsmall molecule where a linear increase in solubilizer will increaseaqueous solubility of a hydrophobic molecule in a logarithmic fashion.As used herein, the term “complexer” means a compound that increases theaqueous solubility of a second compound by associating with the secondcompound.

In some embodiments, a solubilizer comprises a sugar. Examples of sugarsinclude monosaccharides, disaccharides, trisaccharides,oligosaccharides, and polysaccharides. In some embodiments, themonosaccharide is a pentose or furanose monosaccharide ordeoxy-monosaccharide. In some embodiments, the monosaccharide is ahexose or pyranose monosaccharide. Example monosaccharides includeglucose (dextrose), fructose, deoxyfructose, xylose, deoxyxylose,arabinose, deoxyarabanose, ribose, deoxyribose, 2-deoxyribose, ribulose,fucose, fuculose, rhamnose, tagatose, and derivatives thereof. Exampledisaccharides include as sucrose, lactose, maltose, trehalose, andderivatives thereof. Examples of polysaccharides includepolydeoxyribose, starch, lignin, cellulose, and derivatives thereof.Sugars may also include sugar derivatives such as amino-sugars,methyl-sugars, and glycoproteins. Preferred sugars include ribose,2-deoxyribose, deoxyribose, arabanose, ribulose, deoxyarabanose, xylose,deoxyxylose, fructose, deoxyfructose, and analogues thereof.

Some examples of co-solvents include water-miscible liquids. Suchexamples of co-solvents include ethanol, propylene, glycol, polyethyleneglycol, glycerin, 2-pyrrolidone, N-methyl-2-pyrrolidone, and the like.More examples of solubilizers include complexers. Example of complexersinclude nicotinamide and cyclodextrins.

Without wishing to be bound to any one theory, in some embodiments,particular solubilizers, e.g., sugars, in the compositions and methodsdescribed herein promote the solubility of resveratrol and analoguesthereof. For example, some sugars enhance the solubility of certainhydrocarbons based on a co-solvent effect. Such co-solvent effects ofsugars on the aqueous solubilities of hydrocarbons are described, forexample, in Janado et al., (1985) “The Nature of the Co-solvent Effectsof Sugars on the Aqueous Solubilities of Hydrocarbons.” Bull. Chem. Soc.Jpn. 58:1913-1917, which is incorporated herein by reference in itsentirety. Accordingly, in some embodiments, particular sugars and sugarderivatives are selected based on predicted solubilization properties.For example, in some embodiments, sugars having a hydrophobic region anda hydrophilic region are selected.

In some embodiments, particular complexers, e.g., nicotinamide, in thecompositions and methods described herein promote the solubility ofresveratrol and analogues thereof. Without wishing to be bound to anyone theory, in some such embodiments, solubilization can includehydrotrophic solubilization can include stacking complexation;chaotrophy, i.e., the breakdown of water structure; or the formation ofmicellular aggregates. (Sanhvi et al., (2007) “Stacking complexation bynicotinamide: a useful way of enhancing drug solubility.” Int. J. ofPharm. 336:35-41). Accordingly, in some embodiments, a complexer can beselected based on factors that include associations and interactionswhich increase aqueous solubility are also affected by aromaticity andmolecular geometry.

In some embodiments, particular solubilizers, e.g., co-solvents, in thecompositions and methods described herein promote the solubility ofresveratrol and analogues thereof. Without wishing to be bound to anyone theory, in some such embodiments, co-solvents increase aqueoussolubility of hydrophobic molecules by disrupting hydrogen bondinglattice of water. The log/linear model is an example predictor of asolubilizer being a co-solvent where a linear increase in co-solvent inaqueous solution will increase solubility of a hydrophobic molecule in alogarithmic fashion. (Jain et al., (2007) “Solubilization of poorlysoluble compounds using 2-pyrrolidone.” Int. J. of Pharm. 342:1-5).

In certain embodiments, the resveratrol compositions provided hereincomprise a co-solvent system. Certain of such co-solvent systemscomprise, for example, benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. In certainembodiments, such co-solvent systems are used for hydrophobic compounds.A non-limiting example of such a co-solvent system is the VPD co-solventsystem, which is a solution of absolute ethanol comprising 3% w/v benzylalcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/vpolyethylene glycol 300. The proportions of such co-solvent systems maybe varied considerably without significantly altering their solubilityand toxicity characteristics. Furthermore, the identity of co-solventcomponents may be varied: for example, other surfactants may be usedinstead of Polysorbate 80™; the fraction size of polyethylene glycol maybe varied; other biocompatible polymers may replace polyethylene glycol,e.g., polyvinyl pyrrolidone. More example co-solvents include ethanol,propylene, glycol, polyethylene glycol, glycerin, 2-pyrrolidone,N-methyl-2-pyrrolidone, and the like.

As will be understood by one skilled in the art, a solubilizer cancomprise the properties of both a complexer and a co-solvent. Forexample, 2-pyrrolidone and N-methyl-2-pyrrolidone can act as complexantsat low concentrations and as co-solvents at high concentrations.

Nutraceutical and Pharmaceutical Compositions

In certain embodiments, the resveratrol compositions of the presentembodiments may be prepared by including methods such as mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tabletting processes.

In certain embodiments, the resveratrol compositions provided herein areadministered in the form of a dosage unit (e.g., lozenge, patch, gel,tablet, capsule, bolus, chewing gum, paste, etc.). In certainembodiments, such dosage units comprise a resveratrol compositionprovided herein, in a dose from about 1 μg/kg dose/body weight to about50 mg/kg dose/body weight, and from about 2 μg/kg dose/body weight toabout 25 mg/kg dose/body weight, from about 10 μg/kg dose/body weight toabout 5 mg/kg dose/body weight. In certain embodiments, thenutraceutical and/or pharmaceutical agents provided herein areadministered as needed. In certain embodiments, the nutraceutical and/orpharmaceutical agents provided herein are administered at least monthly,at least weekly, or at least daily. In some embodiments, theadministering is at least once daily, at least twice daily, at leastthree times daily, at least four times daily. It is recognized by thoseskilled in the art that the particular dose, frequency, and duration ofadministration depends on a number of factors, including, the biologicalactivity desired, the condition of the subject, and tolerance for thenutraceutical and/or pharmaceutical agent.

In preferred embodiments, the resveratrol compositions provided hereinare prepared for buccal administration. Certain of such pharmaceuticalagents are tablets or dosages formulated in conventional manner. Incertain embodiments, a resveratrol composition is prepared fortransmucosal administration. In certain of such embodiments penetrantsappropriate to the barrier to be permeated are used in the formulation.Some such penetrants are generally known in the art. In moreembodiments, the compositions provided herein are prepared for mucosaldelivery. Routes of mucosal delivery are well known in the art.

In some embodiments, the resveratrol of certain compositions providedherein has increased permeability to oral epithelium, e.g., oral mucosalmembranes. In some such embodiments, adsorbtion and/or absorbtion ofresveratrol in the oral cavity is increased. In some embodiments, theresveratrol of certain compositions provided herein is solubilized in asubject's saliva. In some such embodiments, adsorbtion to the surfacesin the oral cavity and/or absorbtion through the surfaces in the oralcavity of resveratrol is increased. In some embodiments, adsorption ofresveratrol to the sub-mucosa and reticular layer of oral mucosa tissueand portions thereof are retained in the upper oral epithelium andbasement membrane. In some embodiments, the resveratrol compositionsprovided herein further include mucoadhesive polymers to promoteadsorption the mucosa.

In some embodiments, the resveratrol compositions provided hereincomprise a resveratrol taste. In some such embodiments, the tastecomprises a capsaicinoid or black pepper like taste.

In certain embodiments, a resveratrol composition provided herein isadministered to a subject between about 0.1% and 500%, 5% and 200%, 10%and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of an establishedhuman dosage. Where no human dosage is established, a suitable humandosage may be inferred from ED₅₀ or ID₅₀ values, or other appropriatevalues derived from in vitro or in vivo studies.

In certain embodiments, a daily oral transmucosal dosage regimen for asubject comprises a dose of between about 0.1 mg and about 5000 mg ofresveratrol, about 5 mg and about 4000 mg, about 5 mg and about 3000 mg,about 5 mg and about 2000 mg, about 5 mg and about 1500 mg, about 10 mgand about 1000 mg, about 20 mg and about 500 mg, about 30 mg and about200 mg, or about 40 mg and about 100 mg of a compound of the presentembodiments. In certain embodiments, a daily dosage regimen isadministered as a single daily dose. In certain embodiments, a dailydosage regimen is administered as two, three, four, or more than fourdoses.

Dosage amount, interval between doses, and duration of treatment may beadjusted to achieve a desired effect. In certain embodiments, dosageamount and interval between doses are adjusted to maintain a desiredconcentration of compound in a subject. For example, in certainembodiments, dosage amount and interval between doses are adjusted toprovide plasma concentration of a compound of the present embodiments atan amount sufficient to achieve a desired effect. In certain of suchembodiments the plasma concentration is maintained above the minimaleffective concentration (MEC).

In certain embodiments, certain resveratrol compositions provided may bepresented in a pack or dispenser device which may contain one or moreunit dosage forms containing the active ingredient. The pack may forexample comprise metal or plastic foil, such as a blister pack. The packor dispenser device may be accompanied by instructions foradministration. The pack or dispenser may also be accompanied with anotice associated with the container in form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human or veterinary administration. Suchnotice, for example, may be the labeling approved by the U.S. Food andDrug Administration for prescription drugs, or the approved productinsert. Compositions comprising a compound of the present embodimentsformulated in a compatible pharmaceutical carrier may also be prepared,placed in an appropriate container, and labeled for treatment of anindicated condition.

In some embodiments, the composition contains stabilizers andpreservatives are added to improve shelf live. Such stabilizers caninclude coatings to protect the core from degradation by light. In someembodiments, the compositions provided herein include a coating,sweetener, thickener, preservative, coloring, flavoring, binder,cosmetic additive, or penetration enhancer. Examples of sweetenersinclude glucose, fructose, tagatose, and commercially acceptedsweeteners. Examples of thickeners include polysaccharides, starches,vegetable gums, lectins, pectin, or proteins. Examples of preservativesinclude calcium propionate, sodium nitrate, sodium nitrite, disodiumEDTA, BHA and BHT. Examples of colorings include E150, Annato E160b,E40, Betanin, Pandan, FD&C Blue No. 1, FD&C Red No. 40, etc. Examples offlavorings include cinnamon, spearmint, cherry, or other acceptedflavorings. Examples of binders include gum Arabic, gum tragacanth,gelatin, starch, dextrose, or mixtures thereof. Examples of cosmeticadditives include flavor crystals, flavor maskers, or other acceptedmethods. Examples of penetration enhancers include bile salts,surfactants, fatty acids and derivatives, chelators, and chitosan. Insome embodiments, the compositions provided herein include a pHadjusting substance, e.g., an acid or a base. Some embodiments alsoincluding adding a coating to protect the resveratrol from light andpreserve form.

Mucosal Delivery

Certain methods provided herein include mucosal delivery of particularcompositions provided herein. Routes of mucosal delivery are well knownin the art. Preferred methods include oral mucosal delivery. The oralcavity comprises the lips, cheek (buccal), tongue, hard palate, softpalate and floor of the mouth. The lining of the oral cavity is referredto as the oral mucosa, and includes the buccal, sublingual, gingival,palatal and labial mucosae. The mucosal tissues in the cheeks (buccal),the floor of the mouth (sublingual) and the ventral surface of thetongue account for about 60% of the oral mucosal surface area. Thebuccal and sublingual tissues are the primary focus for drug deliveryvia the oral mucosa because they are more permeable than the tissues inother regions of the mouth. The oral mucosa is highly vascularized, andtherefore any of the compositions provided here diffusing into the oralmucosa membranes has direct access to the systemic circulation viacapillaries and venous drainage. Thus, the compositions provided hereinthat are absorbed through the oral mucosa directly enter the systemiccirculation, bypassing the gastrointestinal tract and first-passmetabolism in the liver.

Absorption via the oralmucosa is a passive diffusion process. Bysimplifying the oral mucosa into a hydrophobic membrane, Fick's firstlaw can be used to describe the absorption process (equations 1 and 2):

$\begin{matrix}{P = \frac{D \cdot K_{p}}{h}} & \left( {{Equation}\mspace{14mu} 1} \right) \\{A = {{P \cdot C \cdot S \cdot t} = {\frac{D \cdot K_{p}}{h} \cdot C \cdot S \cdot t}}} & \left( {{Equation}\mspace{14mu} 2} \right)\end{matrix}$where P is permeability coefficient, A is the amount of drug, ie.resveratrol, absorbed, D is the diffusion coefficient of the drug in theoral mucosa, Kp is the partition coefficient of the drug betweendelivery medium and the oral mucosa, h is the thickness of the oralmucosa, C is the free drug concentration in the delivery medium, S isthe surface area of the delivery site on the oral mucosa and t is theduration of drug contacting the oral mucosa.

Parameters such as diffusion coefficient, partition coefficient andthickness of the tissue are inherent properties of the drug, e.g.,resveratrol, and the mucosa. Other parameters, such as surface area,duration of drug delivery and concentration are controlled by the dosageform and formulation. As will be understood, free drug concentration isa consideration when developing transmucosal drug delivery dosagefont's. The effective formulation advantageously releases thecomposition to the mucosal surface, with the drug, e.g., resveratrol, inits free form. If the drug is bound to other components in theformulation, it is not available for transmucosal delivery and thebioavailability will be greatly reduced.

Some compositions and methods provided herein include transmucosaldelivery of drugs such as resveratrol with a variety of dosage forms.Examples of such dosage forms include tablets, lozenges (includinglyophilized and bioadhesive), chewing gum, pastes, solution sprays,laminated systems and patches, hydrogels, adhesive films, hollow fibres,pressure capsules, taffy, freeze-dried solid, and microspheres.

Solid dose formulations can dissolve in the oral cavity, and generally,drugs are released and exposed to the entire mucosa and the top third ofthe oesophageal mucosa. In some embodiments, delivery of compositionsprovided herein can include administering the composition via a routeincluding bucal, sublingual, and gingival routes.

Improved Bioavailability

Certain compositions comprising resveratrol or analogues thereofprovided herein have improved bioavailability as compared to othercompositions and/or routes of administration. In some embodiments,resveratrol compositions are advantageously administered by the oraltransmucosal route. Without wishing to be bound to any one theory, sucha route allow for greater peak plasma levels of unmodified resveratrolby circumventing first pass-metabolism in the small intestine and theliver. Other non-transmucosal routes of administration, such as oraldelivery, result in resveratrol being metabolized in the small intestineand/or liver before the resulting metabolites of resveratrol enter thegeneral circulation. Some embodiments of the compositions providedherein offer further advantages by presenting resveratrol in a form thatis rapidly absorbed in the oral mucosal membrane. In some embodiments,the compositions provided herein provide an increase in bioavailabilityfrom 0.1%-4% as compared to an oral dose or alternative formulation.Some embodiments include an increase of up to or exceeding 20%bioavailability.

In some embodiments, improved bioavailability includes an increasedpercentage of a dose that is absorbed by a subject. In some embodiments,improved bioavailability includes an increased period of time and/or ahigher level of resveratrol that is present in serum as compared to anoral dose or alternative formulation. In some embodiments, improvedbioavailability includes an increased period of time that resveratrol ispresent in serum at higher concentrations, for example, as the peakplasma level increases, then the area under plasma concentration (AUC)for resveratrol is increased as compared to an oral dose or alternativeformulation. In some embodiments, resveratrol metabolites (e.g.,resveratrol monoglucuronides, resveratrol-3-sulfate, and like) areproduced at a later period of time after administration of resveratrol.For example, peak levels of resveratrol metabolites are produced in asubject at a later period after administration of resveratrol. In someembodiments, AUC values for resveratrol metabolites are decreased. Insome embodiments, improved bioavailability includes an increased levelof resveratrol in the serum of a subject, for example an increasedC_(max).

Methods for Improving Bioavailability of Resveratrol

Methods provided herein include methods for improving thebioavailability and peak plasma levels of resveratrol in a subject. Somesuch methods include administering a composition comprising resveratroland a solubilizer as described above to the subject. In preferredembodiments the administering comprises transmucosal delivery. In somepreferred methods, the transmucosal delivery comprises oral transmucosaldelivery.

In some methods for improving the bioavailability of resveratrol oranalogue thereof in a subject, the administering achieves an area underserum concentration (AUC) of resveratrol greater than about 500ng*hr/ml, greater than about 600 ng*hr/ml, greater than about 700ng*hr/ml, greater than about 800 ng*hr/ml, greater than about 900ng*hr/ml, greater than about 1000 ng*hr/ml, greater than about 1100ng*hr/ml, greater than about 1200 ng*hr/ml, greater than about 1300ng*hr/ml, greater than about 1400 ng*hr/ml, greater than about 1500ng*hr/ml, greater than about 1600 ng*hr/ml, greater than about 1700ng*hr/ml, greater than about 1800 ng*hr/ml, greater than about 1900ng*hr/ml, greater than about 2000 ng*hr/ml, greater than about 2100ng*hr/ml, greater than about 2200 ng*hr/ml, greater than about 2300ng*hr/ml, greater than about 2400 ng*hr/ml, greater than about 2500ng*hr/ml, greater than about 2600 ng*hr/ml, greater than about 2700ng*hr/ml, greater than about 2800 ng*hr/ml, greater than about 2900ng*hr/ml, and greater than about 3000 ng*hr/ml. In some embodiments, theadministering achieves an AUC greater than about greater than about 3500ng*hr/ml, greater than about greater than about 4000 ng*hr/ml, greaterthan about greater than about 4500 ng*hr/ml, greater than about greaterthan about 5000 ng*hr/ml, greater than about greater than about 5500ng*hr/ml, greater than about greater than about 6000 ng*hr/ml, greaterthan about greater than about 6500 ng*hr/ml, and greater than aboutgreater than about 7000 ng*hr/ml.

In some methods for improving the bioavailability of resveratrol oranalogue thereof in a subject, the administering achieves a serumC_(max) greater than about 20 ng/ml, greater than about 30 ng/ml,greater than about 40 ng/ml, greater than about 50 ng/ml, greater thanabout 60 ng/ml, greater than about 70 ng/ml, greater than about 80ng/ml, greater than about 90 ng/ml, and greater than about 100 ng/ml. Insome methods for improving the bioavailability of resveratrol oranalogue thereof in a subject, the administering achieves a serumC_(max) greater than about 100 ng/ml, greater than about 200 ng/ml,greater than about 300 ng/ml, greater than about 400 ng/ml, greater thanabout 500 ng/ml, greater than about 600 ng/ml, greater than about 700ng/ml, greater than about 800 ng/ml, greater than about 900 ng/ml, andgreater than about 1000 ng/ml. In some methods for improving thebioavailability of resveratrol or analogue thereof in a subject, theadministering achieves a serum C_(max) greater than about 1000 ng/ml,greater than about 2000 ng/ml, greater than about 3000 ng/ml, greaterthan about 4000 ng/ml, and greater than about 5000 ng/ml.

In some embodiments, the pharmacokinetic values described above may beachieved by using certain of the compositions and/or methods of deliverydisclosed herein. For example, in one embodiment, improved AUC and/orimproved C_(max) are achieved by oral transmucosal delivery using acomposition comprising a high concentration of resveratrol and asolubilizer as described above.

In some methods for improving the bioavailability of resveratrol in asubject, the amount of the resveratrol to solubilizer is in the range ofabout 5 mg/g to about 500 mg/g, about 20 mg/g to about 100 mg/g, 40 mg/gto about 80 mg/g, and 50 mg/g to about 70 mg/g.

In some methods for improving the bioavailability of resveratrol in asubject, the administering is at least monthly, at least weekly, or atleast daily. In some embodiments, the administering is at least oncedaily, at least twice daily, at least three times daily, at least fourtimes daily.

In some methods for improving the bioavailability of resveratrol in asubject, the dosage of the resveratrol is in the range of about 5 mg toabout 10,000 mg or about 50 mg to about 5000 mg.

In some methods for improving the bioavailability of resveratrol in asubject, the final formulation size is in the range of 5 mg to about10,000 mg or about 50 mg to about 5000 mg. In some methods for improvingthe bioavailability of resveratrol in a subject, the compositioncomprises, but is not limited to, a lozenge, chew, chewing gum, gel,taffy, paste, or patch.

Methods of Manufacture

The embodiments provided herein also relate to methods for dissolvingresveratrol and its analogues for clinical application and dietarysupplementation. In some methods for improving the bioavailability ofresveratrol in a subject, the composition is prepared by a methodcomprising: providing as a base carrier, a high molar concentration ofsolubilizers in liquid form; and dissolving the resveratrol in the basecarrier.

In some embodiments, in order to dissolve the resveratrol, highconcentrations of a solubilizer mixture are utilized as a base. Thesolubilizer mixture can be in the form of syrup which is heated in orderto dissolve the resveratrol. Dissolved levels may include 100 mg ofresveratrol per gram of solubilizer syrup. From thissolubilizer/resveratrol mixture as a starting point, solutions may beprepared utilizing various sweeteners, binders, flavoring agents,coloring agents, preservatives, plant polysaccharides, disaccharides,emulsification agents, and/or oils, to optimize the solubility.Alternatively, in some embodiments, no additives are used.

According to some such compositions and methods, resveratrol isincorporated into a base carrier for oral transmucosal delivery. Aparticularly preferred base carrier is made from a high molarconcentration of solubilizer mixture in liquid form into which theresveratrol has been brought into aqueous solution and then solidified.The base carrier can be administered to the individual so that theindividual retains the solubilizer mixture in the mouth, allowing for anincreased amount of resveratrol to be absorbed through the mucousmembranes of the mouth.

In some methods a composition is prepared by a method comprising:heating at least one solubilizer, to decrease its water content therebyforming a solid at room temperature; reheating the solid so produced tomelt the solid and form a base carrier; and adding the resveratrol tothe base carrier. In some embodiments, the solubilizer base is heated inan oven to about 90° C. for about 14 hours to decrease the water contentof the syrup solubilizer base. In some embodiments, the heated syrup wasapproximately ⅕ water by weight and became solid at room temperature. Insome embodiments, the solid was reheated to approximately 90° C. beforeadding the trans-resveratrol.

In some methods the composition is prepared by a method comprising:incorporating the resveratrol into a base carrier that requires chewingor retention in the mouth; the base carrier comprising a high molarconcentration of at least one solubilizer in liquid form into which theresveratrol has been dissolved and later solidified.

The embodiments provided herein also relate to methods for dissolvingresveratrol and its analogues for clinical application and dietarysupplementation. In order to dissolve the resveratrol, highconcentrations of solubilizer is utilized as a base. The solubilizermixture can be in the form of syrup which is heated in order to dissolveand incorporate the resveratrol. Dissolved levels may include 125 mg ofresveratrol per gram of solubilizer syrup. From thissolubilizer/resveratrol mixture as a starting point, solutions may beprepared utilizing various sweeteners, binders, flavoring agents,coloring agents, and/or preservatives.

In some embodiments, the syrup is reheated to the point of solidifying,to thereby produce a solid composition that contains high levels ofresveratrol. In some embodiments, the composition is coated. In someembodiments, a thickener is added to the formulation to assist insolubility and slow the dissolving of the formulation, and allowing formore absorption of the resveratrol in the mouth. In some embodiments,the formulation could also contains additives including but not limitedto vitamin E, quercetin, or caffeine.

EXAMPLES Example—Resveratrol and Fructose/Dextrose

20 g Fructose/Dextrose (90%/10%, m/m) syrup was incubated at about 90°C. for 14 hours. After incubation, the initial syrup had lostapproximately ⅕ weight by water loss and became solid at roomtemperature. The solid was reheated to about 90° C. to melt the solidand the liquid syrup was allowed to cool. Resveratrol (500 mg 98%trans-resveratrol, capsules, Transmax™, Product No. 94922-73528) wasadded to the warm liquid syrup. The composition remained liquid and hada very light capsinoid or black pepper like taste.

A substance in a free form can elicit a taste through contact with thenerves and tissues of the mouth. Resveratrol has little or no taste whenit is dry, dissolved in oil, or suspended in water. In a wet mouth,resveratrol has no taste. Surprisingly, when resveratrol was present inthe fructose/dextrose mixture, it had a distinct, strong, steady lightcapsaicinoid or black pepper like taste.

Example—Reservatrol and Ribose

A ribose/water solution (18 g/2 g) was heated. To the warm solution,resveratrol was added to achieve a final ratio of 100 mg resveratrol to1000 mg solution. On cooling, the liquid provided a hot irritablesensation in the mouth of a subject, comparable to cinnamon. This datamay show that solubility of resveratrol is increased in the presence ofribose.

Example—Resveratrol Solubility in Ribose

Resveratrol solutions were prepared and the solubility determined usingmethods that included U.V. HPLC and mass spectrometry (See e.g., BoocockD, et al. Quantitation of trans-resveratrol and detection of itsmetabolites in human plasma and urine by high performance liquidchromatography. J Chromatogr B 2007; 848:182-7). The solutions included1.6 mg resveratrol in 1 ml water, 1.6 mg resveratrol in 1 ml 3 M ribose,1.6 mg resveratrol in 1 ml water exposed to U.V. light for 30 minutes,and 1.6 mg resveratrol in 1 ml 3 M ribose exposed to U.V. light for 30minutes. The peak areas of the LC traces using U.V. and MS spectraldetection were determined. The percentage increase in the peak area withribose (undiluted) sample was 83.1%. Table 1 summarizes the results.

TABLE 1 Resveratrol Resveratrol Resveratrol Sample UV MS MS/MS 0.4 mg/mlstandard in 32589198 361620189 22825783 MeOH/water 1.3 mg resveratrol in1 ml 3757436 17991728 1055482 water 1.3 mg resveratrol in 1 ml 687904434006422 2177343 1M ribose 1:1 dilution of water sample 7414378 363504912235878 1:1 dilution of ribose sample 10156011 59987321 4277049

Example—Solubility of Resveratrol in 3M Ribose

Resveratrol solutions were prepared and the solubility determined usingmethods that included U.V. HPLC and mass spectrometry. The solutionsincluded 1.6 mg resveratrol in 1 ml water, 1.6 mg resveratrol in 1 ml 3M ribose, 1.6 mg resveratrol in 1 ml water exposed to U.V. light for 30minutes, and 1.6 mg resveratrol in 1 ml 3 M ribose exposed to U.V. lightfor 30 minutes. FIGS. 1-4 show U.V. and MS spectral traces for 1.6 mgresveratrol in 1 ml water, 1.6 mg resveratrol in 1 ml 3 M ribose, 1.6 mgresveratrol in 1 ml water exposed to U.V. light for 30 minutes, and 1.6mg resveratrol in 1 ml 3 M ribose exposed to U.V. light for 30 minutes,respectively. Table 2 and 3 summarize the results.

TABLE 2 Detection method Water 3M ribose % increase PDA (trans-316 nm,cis-284 nm) 10448839 17477801 67.3 Mass spectroscopy 35925663 6922633392.7 Tandem mass spectroscopy 6058729 11603388 91.5

TABLE 3 Detection Water (UV Water (UV Ratio 3M ribose (UV 3M ribose (UVRatio method exposed, trans) exposed, cis) cis/trans exposed, trans)exposed, cis) cis/trans PDA (trans-316 3293034 2260306 0.6864 96679853348277 0.3463 nm, cis-284 nm) Mass 7702267 42202693 5.4793 3005604667794774 2.2556 spectroscopy Tandem mass 1489337 8357052 5.6113 467818312957854 2.7698 spectroscopy

Example—Pharmacokinetic Study

Subjects are administered 100 mg resveratrol by oral transmucosaladministration of a resveratrol/solubilizer formulation (test), by oraladministration of resveratrol/solubilizer mixture (control), or by oraltransmucosal administration of a resveratrol/sucrose formulation(control). Resveratrol levels are measured in the serum and urine of thesubjects at various intervals of time over a 24 hour period. Any adverseeffects are recorded.

Resveratrol and its metabolites are extracted and separate using agradient UV-high-performance liquid chromatography system (Boocock D, etal. “Quantitation of trans-resveratrol and detection of its metabolitesin human plasma and urine by high performance liquid chromatography.” JChromatogr B 2007; 848:182-7). Pharmacokinetic variables are determined(Boococket et al., (2007) “Phase I Dose Escalation Pharmacokinetic Studyin Healthy Volunteers of Resveratrol, a Potential Cancer ChemopreventiveAgent.” Cancer Epidemiol Biomarkers Prev 16(6): 1246-1252). Thefollowing pharmacokinetic variables are calculated for resveratrol andits three major metabolites using a noncompartmental pharmacokineticapproach and the “PhAST” (Phoenix Automated Statistics and Tabulation)validated proprietary software (MDS Pharma Services, 1999): area underthe plasma concentration versus time curve (AUC; by the trapezoidalmethod), maximal plasma concentration (C_(max)) and time of maximalplasma concentration (T_(max)), average concentration over the totalcollection period (C_(av)=_(AUC0-24)/24 h), apparent eliminationhalf-life (ln 2/k_(el), where k_(el) is apparent elimination rateconstant), apparent total clearance (CL/F=dose/AUC_(inf)), apparentrenal clearance of resveratrol (CL_(R); approximated by Ae₀₋₂₄/AUC₀₋₂₄,where Ae₀₋₂₄ is estimated total amount excreted in urine over the totalcollection period), and apparent volume of distribution of resveratrol[V/F=dose/(k_(el)×AUC_(inf))]. For a few subjects, pre-dose samplescontain peaks coeluting with resveratrol or its metabolites. In thesecases, AUC and C_(max) values are adjusted assuming these peaksconstituted pre-dose concentrations (C₀) of resveratrol or resveratrolmetabolite. These adjustments are made using the formulasAUC_(infcorr)=AUC_(infobs)−C₀/k_(el) andC_(maxcorr)=C_(maxobs)−(C₀×e−^(kel)×T_(max))).

Results

Resveratrol administered with a resveratrol/solubilizer formulation bythe oral transmucosal route achieves a greater peak plasma level andbioavailability than the oral transmucosal resveratrol/sucroseformulation (control) or the resveratrol/solubilizer formulation takenthrough the oral route (control).

Peak levels of resveratrol metabolites (e.g., resveratrolmonoglucuronides and resveratrol-3-sulfate) in the serum of testsubjects are initially detected at a lower level than peak levels ofresveratrol metabolites in the serum of control subjects.

AUC values for resveratrol metabolites are lower in test subjects thanAUC values for resveratrol metabolites in control subjects.

Serum C_(max) levels of resveratrol are higher in test subjects thanserum C_(max) levels of resveratrol in control subjects.

Table 4 shows estimated pharmacokinetics of resveratrol and twometabolites that are predicted from the plasma of test and controlsubjects administered 100 mg resveratrol (Almeida, et al. (2009)“Pharmacokinetic safety profile of trans-resveratrol in a risingmultiple-dose study in healthy volunteers.” Mol Nutr Food Res. 53 Suppl1:S7-15).

FIG. 5 shows an estimated time-concentration profile of serumresveratrol concentration that is predicted in a subject administered100 mg resveratrol by an oral route (Boocock et al., (2007) “Phase IDose Escalation Pharmacokinetic Study in Healthy Volunteers ofResveratrol, a Potential Cancer Chemopreventive Agent.” Cancer EpidemiolBiomarkers Prev 16:1246-1252).

TABLE 4 Test Control(s) Resveratrol AUC_(inf) (ng * hr/ml) 30 19.5C_(max) (ng/ml) 50 21 T_(max) (hr) 0.3 1.3 C_(av) (ng/ml) 12 8 Half-life(hr) 2.8 2.8 Glucuronide 1 AUC_(inf) (ng * hr/ml) 300 380 C_(max)(mg/ml) 70 80 T_(max) (hr) 3.5 2.0 C_(av) (ng/ml) 14 16 Half-life (hr)3.0 2.8 3-sulfate AUC_(inf) (ng * hr/ml) 700 800 C_(max) (mg/ml) 150 227T_(max) (hr) 3.0 1.5 C_(av) (ng/ml) 23 34 Half-life (hr) 3.0 3.2

Comparative Example—Resveratrol and Sucrose

Resveratrol was added to a sucrose/water solution (1:1 v/v). Theresveratrol failed to dissolve in the solution.

In another experiment, various sucrose/water mixtures were heated toboiling point. Reservatrol was added to each sucrose/water solution. Onheating the mixtures to about 90° C., the mixtures formed thick yellowsyrups, similar to mixtures of resveratrol and 90% fructose/10% dextrosem/m syrup. On cooling, resveratrol/sucrose/water mixtures formedcrystalline solids composed of small crystals; in contrast, thesucrose/water solution formed a crystalline solid composed of largecrystals. All resveratrol/sucrose/water mixtures failed to dissolveresveratrol in a similar fashion due to crystallization.

In another experiment, water was added to the solidresveratrol/sucrose/water mixtures. In each case the resveratrolprecipitated out of solution.

These experiments demonstrate that resveratrol is not soluble in in thepresence of all sugars. However, surprisingly, resveratrol was found tobe soluble in ribose and in fructose/dextrose as exemplified above.These results demonstrate co-solvent sugars such as ribose can achievesurprising and superior results.

Comparative Example—Resveratrol and Dextrose

An aqueous solution of dextrose was prepared and heated to boiling. Theresveratrol was added to the warm syrup and allowed to cool further.While still liquid, the syrup retained a capsinoid flavor. On coolingfurther, a white powdery mixture of crystals was formed. Nocapsinoid-like flavor was detected when the solid mixture was tasted.

This experiment further demonstrates that resveratrol is not wellsoluble in the presence of all sugars and the surprising and superiorresults obtained with co-solvent sugars

Comparative Example—Resveratrol and Sugar Alcohols

Resveratrol was added to warm solutions of xylitol or erythritol. Theresveratrol was observed not to dissolve. On cooling the xylitol orerythritol solution formed a crystalline solid that appeared to excludethe resveratrol. No capsaicirioid-like flavor was detected when eachreservatrol/xylitol and reservatrol/erythritol solid mixture was tasted.

Water was added to the each reservatrol/xylitol andreservatrol/erythritol mixture. However, in each case the resveratrolprecipitated out of solution.

These experiments demonstrate that resveratrol is not soluble in thepresence of particular sugar alcohols. In contrast, superior results areobtained in the presence of co-solvent sugars such as ribose.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps. Allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

What is claimed is:
 1. A pharmaceutical composition comprisingresveratrol and a solubilizer in a buccal, sublingual or gingival dosageform, wherein said solubilizer is selected from the group consisting ofribose, arabinose, glucose, deoxyribose and mixtures thereof, wherein anamount of said resveratrol to solubilizer in the dosage form of saidpharmaceutical composition in in the range of about 5 mg/g to about1,000 mg/g.
 2. The pharmaceutical composition of claim 1, wherein anamount of said resveratrol to solubilizer in the dosage form of saidpharmaceutical composition is in the range of about 20 mg/g to about 100mg/g.
 3. The pharmaceutical composition of claim 1, wherein the dosageform is selected from the group consisting of a tablet, a solid lozenge,a semisolid lozenge, a taffy, a thin film, a capsule, a patch, a gel, abolus, a chewing gum, a paste, a syrup, and a freeze dried solid.
 4. Thepharmaceutical composition of claim 3, wherein the dosage form is asolid lozenge.
 5. The pharmaceutical composition of claim 1, wherein thedosage form further comprises a coating.
 6. The pharmaceuticalcomposition of claim 5 wherein the coating is impermeable to light. 7.The pharmaceutical composition of claim 3, wherein the amount ofresveratrol in the dosage form is about 100 mg.
 8. The pharmaceuticalcomposition of claim 1, wherein the dosage form is suitable for buccaldelivery.
 9. The pharmaceutical composition of claim 1, wherein theratio of resveratrol to solubilizer in the dosage form of thepharmaceutical composition is in the range of about 5 mg/g to about 500mg/g.
 10. The pharmaceutical composition of claim 9, wherein the ratioof resveratrol to solubilizer is in the range of about 20 mg/g to about100 mg/g.
 11. The pharmaceutical composition of claim 1, furthercomprising a sweetener, a thickener, a preservative, a coloring agent, abinder, a flavorant, a penetration enhancer, or a combination thereof.12. The pharmaceutical composition of claim 1 further comprising apenetration enhancer selected from the group consisting of a bile salt,a surfactant, a fatty acid derivative, a chelator and chitosan.
 13. Thepharmaceutical composition of claim 1 further comprising a penetrationenhancer.
 14. The pharmaceutical composition of claim 1 furthercomprising a binder.
 15. A pharmaceutical composition comprisingresveratrol and a solubilizer in a buccal, sublingual or gingival dosageform suitable for enhancing serum bioavailability of resveratrol in asubject, wherein said solubilizer is selected from the group consistingof ribose, arabinose, glucose, deoxyribose and mixtures thereof, andwherein an amount of said resveratrol to solubilizer in the dosage formof said pharmaceutical composition is in the range of about 20 mg/g toabout 100 mg/g.
 16. A pharmaceutical composition comprising resveratroland a solubilizer in a buccal, sublingual or gingival dosage formsuitable for enhancing serum bioavailability of resveratrol in asubject, wherein said solubilizer consists essentially of ribose,arabinose, glucose, deoxyribose or mixtures thereof, and wherein anamount of resveratrol to solubilizer in the dosage form is in the rangeof about 20 mg/g to about 100 mg/g.
 17. The pharmaceutical compositionof claim 14 wherein the binder is sucrose.
 18. The pharmaceuticalcomposition of claim 14 wherein the binder is sucrose, gum arabic, gumtragacanth, gelatin, starch, dextrose, or a mixture thereof.
 19. Thepharmaceutical composition of claim 1, wherein the percentage weight ofthe solubilizer is in the range of about 2% to about 99% by weight of adosage form of said pharmaceutical composition.
 20. The pharmaceuticalcomposition of claim 19, wherein the percentage weight of thesolubilizer is in the range of about 5% to about 95% by weight of adosage form of said pharmaceutical composition.
 21. The pharmaceuticalcomposition of claim 1, wherein resveratrol comprises from about 1% toabout 50% by weight of the dosage form of said pharmaceuticalcomposition.